Benzofuran diamidine compounds

ABSTRACT

New diamidine compounds having trypanocidal action and corresponding to the general formula   IN WHICH R represents hydrogen or lower alkyl, and X represents oxygen, -NH- or -CH2- and salts of these compounds with inorganic or organic acids.

United States Patent Dann Sept. 5, 1972 [54] BENZOFURAN DIAMIDINE Primary Examiner-Alex Mazel COMPOUNDS Assistant Examiner-Bemard Dentz [72] Inventor: Otto Dann, c/o Farbrverke Hoechst Attorney cums Moms & Safford AG., Frankfurt am Main, Germany 57] ABSTRACT [22] Filed: Apnl 1970 New diamidine compounds having trypanocidal action [2] 1 App]. No.: 43,263 and corresponding to the general formula Related US. Application Data [62] Division of Ser. No. 731,287, May 22, 9168, EN R NH Pat. No. 3,652,591. CZNHZ [30] Foreign Application Priority Data X May 26, 1967 Germany ..D 53173 in which R represents hydrogen or lower alkyl, and X CCll. ..260/346.2 It, represents oxygen or and Salts of I 58] Fie'ld /346 2 R these compounds with inorganic or organic acids.

[56] References Cited 4 Claims, No Drawings FOREIGN PATENTS OR APPLICATIONS l,5()2,346 I967 France BENZOFURAN DIAMIDINE COMPOUNDS This application is a division of application Ser. No. 731,287 filed May 22, 1968 now US. Pat. No. 3,652,591.

The present invention relates to new diamidine compounds and to a process for preparing them.

More especially, the present invention provides new diamidine compounds of the general formula 1 C-NHa in which R represents hydrogen or lower alkyl, and X represents oxygen, NI-I or -CH and salts of these compounds with inorganic or organic acids.

The present invention also provides a process for preparing the new diamidine compounds, wherein a dicyano compound of the general formula II NO OH in which R and X have the meanings given above, is converted by means of dry hydrogen halide in an anhydrous solvent in the presence of an alkanol of the generalformula Alk OH, in which ALk represents lower alkyl, into a diimino either of the general formula III Hal.HN N H.Ha1

/C C Alk. O.AIK

in which R and X have the meanings given above, and in which Alk stands for low molecular weight alkyl and Hal stands for halogen, and the diimino ether is reacted with dry ammonia gas in an anhydrous solvent.

The diamidine compounds prepared according to the invention are distinguished by a strong trypanocidal action which is directed against trypanosomes that are pathogenic to humans, for example Trypanosoma rhodesiense and Trypanosoma gambiense, as well as against trypanosomes that are pathogenic to animals,

I for example Trypanosoma congolense.

B 6-amidino-2-(4'-amidino-phenyl)-indenedihydrochloride C S-amidino-2-(4"-amidino-phenyl)-benzofuranedihydrochloride D 5-amidino-3-methyl-2-(4'-amidino-phenyl)- benzofuranedihydrochloride E I4,4'-diamidino-diphenoxy-pentane-bis-(B- hydroxyethanesulfonate F (carbonyl-bis- 8-[3-(3-ammo-benzamido)-4- methyl-benzamido]-naphthalene-trisulfonic acid- 1,3,5)

TABLE 1 Number Substance mg/kg Number of mice of surtreated viving mice after 6 weeks A l (subcutaneously) 6 6 0.5 (subcutaneously) 6 6 0.25 (subcutaneously) 6 4 (perorally) 6 6 Infection control 12 0 B 2 (subcutaneously) 6 6 I (subcutaneously) 6 6 0.5 (subcutaneously) 6 6 B 64 (perorally) 6 6 l6 (perorally) 6 5 Infection control 12 0 C 2 (subcutaneously) 6 6 l (subcutaneously) 6 6 0.5 (subcutaneously) 6 6 64 (perorally) 6 6 l6 (perorally) 6 5 Infection control l2 0 D l (subcutaneously) l6 I6 05 (subcutaneously 16 16 0.25 (subcutaneously)l6 10 I00 (perorally) 6 6 l0 (perorally) 6 3 Infection control 32 0 E 2 (subcutaneously) 6 6 l (subcutaneously) 6 6 0.5 (subcutaneously) 6 2 Infection control l2 0 F 2 (subcutaneously) 6 5 l (subcutaneously) 6 3 Infection control 12 0 As is evident from the above Table, the compounds of thepresent invention have a stronger trypanocidal action than the two known trypanocidal compounds.

The new compounds also show a good action when administered perorally. In contradistinction thereto, the known compounds and the 6-amidino-2-(4'- amidino-phenyl)-thionaphthene described in German Pat. No. 1 234 228 show no action when administered perorally.

The action of the compound 6-amidino-2-(4'- amidino-phenyl)-indol-dihydrochloride prepared according to the present invention against the strain Trypanosoma congolense which is pathogenic to animals was compared in experiments with that of the compound 4,4'-diamidino-aminobenzene.

Mice were treated subcutaneously 2 hours after infection by 6-amidino-2-(4'-amidino-phenyl)-indoldihydrochloride and with 4,4'-diamidinodiazoaminobenzene, respectively. The animals were observed for 9 weeks after the infection. The results are compiled in the following Table 2.

Strain: Trypanosoma congolense Substance A 6-amidino-2-(4'-amidino-phenyl)- indol-dihydrochloride Substance B 4,4-diamidino-diazoaminobenzene TABLE 2 Substance mg/kg, sub- Number of mice number of surviving cutaneously treated mice after 9 weeks A 20 l l0 9 10 10 1 4,5 10 9 B 10 l0 l0 9 10 7 The data compiled in the above Table show that 6- amidino-2-(4'-amidino-phenyl)-indol-dihydrochloride has a stronger trypanocidal action than 4,4 -diamidinodiazoaminobenzene. The compounds [4,4-diamidinodiphenoxypentane-bis-( B-hydroxy-ethanesulfonate (carbonyl-bis- {8-[ 3-( 3-amino-benzamino)-4-methylbenzamino]-naphthalene-trisulfonic acid-( 1,3,5) and the 6-amidino-2-(4'-amidino-phenyl)-thionaphthene described in the German Pat. No. 1' 234 228 practically have no action against Trypanos oma congolense.

For therapeutic use, the acid addition salts with non toxic acids, for example with hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, succinic acid, lactic acid, maleic acid and isothionic acid, may be used.

The dinitrile compounds required as the starting substances may be obtained according to known methods.

The following Examples illustrate the invention but they are not intended to limit it thereto:

EXAMPLE 1:

5-Amidino-2-(4-amidino-phenyl)-benzofuranedihydrochloride A solution of 2 g (0.0082 mol) of 5-cyano-2-(4- cyanophenyl)-benzofurane in 200 ml of anhydrous chloroform was combined with 10 ml (0.18 mol) of absolute ethanol. Then, dry HCl gas was introduced for 3 hours into the solution which after saturation with hydrogen chloride, was poured into a pressure bottle and shaken for 8 days. The precipitate that had formed was separated by filtration with suction and washed with dry ether and petroleum ether. After drying under reduced pressure over phosphorous pentoxide and potassium hydroxide, 3.3 g (98.5 percent of the theoretical yield) of the faintly yellow hydrochloric diimino-ether were obtained.

200 ml of absolute ethanol were saturated with dry ammonia gas and then combined with the dried diimino-ether. The reaction mixture was shaken for 8 days and the precipitate that formed was filtered off with suction. The yellow salt was dried over phosphorus pentoxide and potassium hydroxide at 20 C. For removing any still adhering hydrogen chloride gas and water, the salt was dried for 24 hours under reduced pressure at 90 C over phosphorus pentoxide and potassium hydroxide.

2.28 g (79 percent of the theoretical yield) of yellow colored 5-amidino-2(4'-amidino-phenyl)-benzofuram-dihydrochloride melting at 355 358 C (decomposition) were obtained.

The 5 -amid ino-2-(4'-amidino-phenyl)-benzofuranediisoethionate was found to melt at 285 289C. It dissolved at room temperature in water to give a percent solution.

The 5-amidino-2-(4-amidino-phenyl)-benzofuranedilactate was found to melt at 287 289 C with decomposition. It dissolved at room temperature in water to give a 0.45 percent solution.

The starting products prepared according to known EXAMPLE 2;

5-Amidino-3-methyl-2-(4-amidino-phenyl)- benzofurane-di-hydrochloride A solution of 1.55 g (0.006 mol) of 5-cyano- 3- methyl-2-(4'-cyano-phenyl)-benzofurane in ml of dry chloroform was combined with 8 ml (0.142 mol) of absolute ethanol. Then, dry HCl gas was introduced for 2 hours into the solution. The solution that had saturated with hydrogen chloride was introduced into a pressure bottle and shaken for 6 days. 'The precipitate that formed was transfered with the reaction mixture into a round flask and the solvent was removed with precaution under reduced pressure, in a rotatory evaporator. The imino-ethyl-ether hydrochloride that formed was immediately subjected to further treatment.

The imino-ethyl ether hydrochloride was combined with ml of absolute ethanol saturated with ammonia and the reaction mixture'was shaken in a pressure bottle for a week. The yellow precipitate that formed was filtered under suction, washed with 2N- hydrochloric acid, and dried in vacuum at 20C. over phosphorus pentoxide and potassium hydroxide. Drying over these agents was continued for 24 hours at 90C. to remove any hydrogen chloride and water still present.

2.0 g (91.3 percent of the theoretical yield) of yellow 5-amidino-3-methyl-2-(4'-amidinophenyl)-benzofuran-dihydrochloride were .obtained. m.p. 360 365C. (with decomposition).

The starting materials, obtained according to known methods, had the following; melting points:

5-bromo-3-methyl-2-(4'-nitrophenyl)-benzofuran: l88- C.;

S-bromo-3-methyl-2-(4-aminophenyl)-benzofuran: 110 l1lC.;

5-bromo-3-methyl-2-(4'-bromophenyl)-benzofuran: 146 148 C.;

5-cyano-3-methyl-2-(4'-cyanophenyl)-benzofuran: 257 258 C.

EXAMPLE 3 6-Amidino-2-(4'-amidinophenyl)-benzofurandihydrochloride A solution of 2 g (0.0082 mol) of 6-cyano-2-(4'- cyanophenyl)-benzofuran in 100 ml of dry chloroform was combined with 10 ml (0.18 mol) of absolute alecho] in a pressure bottle. Dry HCl gas was then introduced into the solution for 3 hours. The solution, saturated with hydrogen chloride, was shaken for 6 days. The precipitate formed was then suction-filtered and washed with dry ether and petroleum ether. The weakly yellow colored imino-ethyl-ether hydrochloride was immediately subjected to further treatment.

The imino-ethyl-ether hydrochloride, still damp with solvent, was combined with 160 ml of absolute ethanol saturated with ammonia and the reaction mixture was shaken in a pressure bottle for 6 days. The weakly yellow precipitate that had formed was filtered off and the solvent was removed by distillation in a rotary evaporator. The yellow precipitate was made into a paste with 30 ml of 2N hydrochloric acid and the salt formed was filtered off. The salt was dried for 24 hours over phosphorus pentoxide and potassium hydroxide under reduced pressure at 20 C and for 24 hours under reduced pressure at 90 C. v

2.1 g (72.8 percent of the theoretical yield) of yellow 6-amidino-2-(4-amidino-phenyl)benzofuranedihydrochloride were obtained. The compound was found to start sintering at 230 C and to melt at 265 C. It decomposed upon further heating to above 370 C.

The starting substances obtained according to known methods had the following melting'points:

EXAMPLE 4:

6-Amidino-2-(4'-amidino-phenyl)-indoldihydrochloride 10 g of 6-cyano-2-(4'-cyano-phenyl)-indol were dissolved in 230 ml of glycol-monomethyl ether by heating. Dry HCl gas was introduced until saturation into the cooled solution with exclusion of moisture, while cooling in a water bath. The HCl-saturated solution was poured into a dry pressure bottle, the stopper was fastened and the bottle was shaken mechanically for 3 days. The suspension that had formed was diluted with 100 150 ml of methanol and centrifuged for 30 minutes. After decanting of the solvent, the precipitate was stirred several times with anhydrous petroleum ether, decanted again and finally filtered off with suction. .The magna-like imino-ether hydrochloride which was still wet from petroleum ether was transferred into a bottle having a capacity of 1 liter, combined with 400 ml of absolute alcohol saturated with ammonia and shaken mechanically for 7 days. The diamidine that precipitated was filtered off with suction and stirred vigourously for about half an hour in a beaker with about 800 ml of 2N HCl. The diamidinedihydrochloride that formed was again filtered off with suction and dried in a vacuum desiccator at first for 2 days over KOl-l, then for a further 2 3 days over potassium hydroxide and phosphorus pentoxide, until complete dryness.

Yield: 12 g (83.5 percent of the theoretical yield) of yellow 6-amidino-2-(4'-amidino-phenyl)-indoldihydrochloride melting at 360 362 C with decomposition.

EXAMPLE 5:

6-Amidino-2-(4'-amidino-phenyl)-indol-dilactate 250 g of the ion exchanger Merck lIl, strongly basic were filled into a column having a diameter of about 6 cm and a'length of 35 cm, and saturated with about 800 ml of 20 percent ammonium lactate solution.

A solution, prepared at room temperature, of. 10 g of percent of the theoretical yield) of yellow dilactate which was found to melt at 219 222 C. The

solubility in water at 20 C was 60 percent. The aqueous solution showed a neutral reaction.

The diacetate had a melting point of 250 253 C (decomposition). The solubility in water at 20 C was 6.5 percent. The aqueous solution showed a neutral reaction.

EXAMPLE 6:

5-Amidino-2-(4-amidino-phenyl)-indoldihydrochloride 4 g of 5-cyano-2-(4'-cyano-phenyl)-indol were dissolved in 250 ml of nitrobenzene by heating. The solution was cooled in a water bath, whereby the substance precipitated partly. 50 ml of absolute alcohol were added to the suspension and then dry HCl-gas was introduced until saturation under exclusion of moisture,

while cooling in a water bath. The l-lCl-saturated solution was poured into a pressure bottle and shaken mechanically for 12 days. The imino-ether hydrochloride that separated wasfiltered off with suction, washed with anhydrous ether and anhydrous petroleum ether until it was largely free from HCl and transferred into a pressure bottle. 200 ml of absolute alcohol saturated with ammonia were added and the reaction mixture was shaken for 7 days. The diamidine that separated was filtered off with suction and stirred vigorously for about half an hour with 300 400 ml of 2N HCl. The diamidine-dihydrochloride that formed was filtered off with suction and dried in a vacuum desiccator for l 2 days over potassium hydroxide, then for a further 2 3 days over potassium hydroxide and phosphorus pentoxide until complete dryness. 3.1 g 54 percent of the theoretical yield) of S-amidino- 2-(4-amidino-phenyl)-indol-dihydrochloride melting at 360 364 C with decomposition were obtained.

EXAMPLE 7:

6-Amidino-2-(3'-amidino-phenyl)-indoldihydrochloride 1.45 g of 6-cyano-2-(3'-cyano-phenyl)-indol were dissolved in 45 ml of nitrobenzene by heating. The cooled solution was combined with 18 ml of absolute alcohol and then dry HCl gas was introduced until saturation under exclusion of moisture, while cooling in a water bath. The solution saturated with hydrogen chloride was introduced into a pressure bottle and shaken mechanically for 5 days. The imino-ether hydrochloride that precipitated was filtered off with suction, washed on the filter with anhydrous ether and anhydrous petroleum ether until it was largely free from HCl and poured into a pressure bottle. After addition of 80 ml of absolute alcohol saturated with ammonia, the whole was shaken mechanically for 7 days. The diamidine that precipitated was filtered off with suction and stirred vigorously for about half an hour with about 150 ml of 2N HCl. The diamidinedihydrochloride that formed was filtered off with suction and dried in a vacuum desiccator for 1 2 days over potassium hydroxide, then for a further 1 2 days over potassium hydroxide and phosphorus pentoxlde until complete dryness. 1.1 g 53 percent of the theoretical yield) of 6-amidino-2-(3amidino-phenyl)- indol-dihydrochloride melting at 331 333 C with decomposition was obtained.

EXAMPLE 8:

-Amidino-2-( 3'-amidino-phenyl)-indoldihydrochloride 1.7 g of 5-cyano-2-(3-cyano-phenyl) indol were dis- A solved in 90 ml of nitrobenzene while heating. The

solution was cooled on a water bath, whereby the substance precipitated partly. The suspension was combined with 22 ml of absolute alcohol and then dry l-lCl gas was introduced until saturation under exclusion of 'suction,'washed with anhydrous ether and anhydrous petroleum ether until it was largely free from HCl and transferred into a dry pressure bottle. Then, 100 ml of absolute alcohol saturated with ammonia were added and the whole was shaken mechanically for 7 days. The diamidine that precipitated was filtered off with suction and stirred vigorously for about half an hour with 150 200 ml of 2N HCl. The diamidine-dihydrochloride that formed was filtered off with suction and dried in a vacuum desiccator for 1 2 days over potassium hydroxide, then for a further 2 3 days over potassium hydroxide and phosphorus pentoxide until complete dryness.

1.5 g (61 percent of the theoretical yield) of 5- amidino-2-( 3 '-amidino-phenyl)eindol-dihydrochloride, melting at 290 298 C with decomposition, were ob tained.

The starting products prepared according to known methods had the following melting points:

6-bromo-2-(4'-bromo-phenyl)-indol: 193 194 C 5-bromo-2-(4'-bromo-phenyl)-indol: 204 206 C 6-bromo-2-( 3 -bromo-phenyl)-indol: 123 125 C 5-bromo-2-(3'-bromo-phenyl)-indol: 147 148 C 6-cyano-2-(4'-cyano-phenyl)-indol: 283 284 C 5-cyan0-2-(4'-cyano-phenyl)-indol: 309 310 C 6-cyano-2-(3-cyano-phenyl)-indol: 230 232 C 5-cyano-2-( 3-cyano-phenyl)-indol: 256 258 C EXAMPLE 9:

6-Amidino-2-(4'-arnidino-phenyl)-indenedihydrochloride Dry hydrogen chloride gas was introduced until saturation into a solution of 4.5 g (19 mmols) of 6-cyano-2- (4'-cyano-phenyl)-indene, melting at 239 241 C, in 250 ml of anhydrous chloroform and 250 ml of ethanol. The solution was then poured into a pressure bottle and stirred mechanically for 12 days. The

was filtered and the diamidine-dihydrochloride was,

precipitated from the clear solution by adding 250ml of 2N hydrochloric acid while stirring. The yellow product that had precipitated was filtered off and dried under reduced pressure for 48 hours over potassium hydroxide. 4.5 g (68 percent of the theoretical yield) of 6-amidino-2-(4-amidino-phenyl)-benzofuranedihydrochloride which, upon heating, turned dark from about 250 C on, and which carbonized while melting when heated to 360 C., were obtained.

EXAMPLE 10:

In a manner analogous to thatdescribed inExample 9, 3-methyl-6-amidino-2-(4'-amidinophenyl)-indenedihydrochloride was obtained in a yield of 70 percent from 3-methyl-6-cyano-2-(4-cyano-phenyl)-indene (melting point 226 228 C). The 3-methyl-6- amidino-2-(4-arnidino-phenyl)indenedihydrochloride had a yellow color and, when heated, it turned dark from about 250 C on and carbonized with melting when heated to 360C.

EXAMPLE 11:

In a manner analogous to that described in Example 9, 3-ethyl-6-amidino-2-(4'-amidinophenyl)-indene hydrochloride was obtained in a 40 percent yield from 3-ethyl-6-cyano-2-(4-cyanophenyl)-indene (mp. 188 190 C.). The 3-ethyl-6-amidino-2-(4'-amidino-phenyl)-indene-dihydrochloride had a yellow color. When heated it turned dark from about 250C on and carbonized with melting when heated to 360 C.

EXAMPLE 12;

In a manner analogous to that described in Example 9, 3-n-propyl 6-amidino-2-(4'-amidino-phenyl)-indene-dihydrochloride was prepared in a yield of 65 percent from 3-n-propyl-6-cyano-2-(4-cyanophenyl)-indene (m.p. 157 C.). The 3-n-propyl-6-amidino- 2-(4-amidino-phenyl)-indene-dihydrochloride had a yellow color and, when heated, it turned dark from about 250 C on and melted at about 345 C. The starting substances required for preparing the above compounds were obtained according to known methods.

We claim:

1. A diamidine compound of the formula NHr , 9 wherein the amidino group is in the five-position or six- 3. 5-amidino-3-methyl-2-(4-amidinophenylposition in the benzofuran ring and R is alkyl having benzofurane and pharmaceutically acceptable acid adone to three carbon atoms, and pharmaceutically acditiofl Salts thereofceptable acid addition salts th f, 4. 6-amidino-2-(4'-amidinophenyl)-benzofurane and 2. 5-amidin0-2-( 4 -amidinophenyl)-benzofurane and 5 pharmaceutically acceptable acid addition Salts pharmaceutically acceptable acid addition salts thereof thereof. 7 a: in 

2. 5-amidino-2-(4''-amidinophenyl)-benzofurane and pharmaceutically acceptable acid addition salts thereof.
 3. 5-amidinO-3-methyl-2-(4''-amidinophenyl-benzofurane and pharmaceutically acceptable acid addition salts thereof.
 4. 6-amidino-2-(4''-amidinophenyl)-benzofurane and pharmaceutically acceptable acid addition salts thereof. 